Novel process for the preparation of acylguanidines and acylthioureas

ABSTRACT

The present invention relates to a novel process for the preparation of compounds of general formula (I) 
     
       
         
         
             
             
         
       
     
     and the salts thereof, particularly the physiologically acceptable salts thereof with inorganic or organic acids and bases, which have valuable pharmacological properties, particularly an inhibitory effect on epithelial sodium channels, the use thereof for the treatment of diseases, particularly diseases of the lungs and airways.

The present invention relates to a novel process for the preparation ofcompounds of general formula (I)

and the tautomers and the salts thereof, particularly thepharmaceutically acceptable salts thereof with inorganic or organicacids and bases, which have valuable pharmacological properties,particularly an inhibitory effect on epithelial sodium channels, the usethereof for the treatment of diseases, particularly diseases of thelungs and airways,comprising intermediates of general formula (III) and optionally (II)and/or (IV).

BACKGROUND TO THE INVENTION

Compounds of formula (I) are known from the prior art as activesubstances for example for the treatment of diseases of the lungs andairways (J. Med. Chem. 49 (2006) 4098-4115). Processes for preparingcompounds of formula (I) from compounds of formula (III) withR^(t)=methyl (Laeckmann, D. et al. Bioorg., Med. Chem. 10 (2002)1793-1804) or from compounds of formula (IV) (J. Med. Chem. 49 (2006)4098-4115) are known from the prior art.2-Tert-butyl-5-methyl-1,2-oxazol-2-ium perchlorate(tert-butyl-methylisoxazolium perchlorate), also referred to as“Woodward's reagent L” is known from the prior art as an intermediatefor the synthesis of compounds of formula (III) (Laeckmann, D. et al.Bioorg. Med. Chem. 10 (2002) 1793-1804). Due to the known oxidizingproperties of the perchlorate ion, the use oftert-butyl-methylisoxazolium perchlorate may constitute a substantialhazard, especially when applied in larger scale. The “Recommendations onthe transport of dangerous goods; Manual of Tests and Criteria (UnitedNations, 5^(th) revised ed. 2010; appendix 6, page 440, Table A6.1)”list the perchlorate moiety as a group indicating explosive propertiesin organic materials. No salts of the2-tert-butyl-5-methyl-1,2-oxazol-2-ium ion other than the perchlorateare known from the literature.

The preparation of compounds of formula (IV) from compounds of formula(III) is known from the prior art (Shepard, K. L. et al. J. HeterocyclicChem. 13 (1976) 1219-1224). The preparation of compounds of formula (IV)from compounds of formula (V)

R¹—COOH  (V)

without generating compounds of formula (III) as intermediates isdescribed in WO2009074575. The reaction described therein requires thecoupling reagent O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU) which is regarded as a potential explosive.

The problem of the present invention is to provide a process, whichavoids the use of highly hazardous intermediates or reagents, forpreparing compounds of formula (I).

Especially the problem of the present invention is to provide a process,which avoids the use of highly hazardous intermediates, for preparingcompounds of formula (III) or (IV).

Especially the problem of the present invention is to provide a processfor preparing compounds of formula (I) without the use of2-tert-butyl-5-methyl-1,2-oxazol-2-ium perchlorate, other perchloratesalts, perchloric acid, HATU,O-(Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate(TBTU) or other reagents based on 1-hydroxy-7-azabenzotriazole (HOAt) or1-hydroxybenzotriazole (HOBT) or hydrogen sulphide. In order to avoidhighly hazardous intermediates the exothermic decomposition energy ofreagents and intermediates applied in the process should be less than2000 J/g and the onset of exothermic decomposition (if applicable)should be above 180° C. (For comparison: Differential Scanningcalorimetry data (Closed gold vessel) for2-tert-butyl-5-methyl-1,2-oxazol-2-ium perchlorate (“Woodward's reagentL”): Exothermic event of ΔH=4395 J/g and T_(onset)=158° C.)

DESCRIPTION OF THE INVENTION

The present invention solves the above-mentioned problems by the methodof synthesis described hereinafter.

The invention thus relates to a process for the preparation of compoundsof general formula (I)

optionally in the form of the tautomers thereof, and optionally the acidaddition salts thereof, wherein

R¹ denotes a group of formula (i),

-   -   wherein    -   A¹ and A² independently from each other denote N or CH;    -   R^(1.1) denotes hydrogen or a group selected from among chloro,        bromo and methyl,    -   R^(1.2) denotes hydrogen or a group selected from among amino,        C₁₋₃-alkyl-NH—, (C₁₋₃-alkyl)₂N— and methyl,    -   or    -   R^(1.1) and R^(1.2) together form an annelated benzo ring;    -   R² denotes hydrogen or a group selected from among C₁₋₆-alkyl,        C₆₋₁₀-aryl-C₁₋₆-alkyl-, heterocyclyl and heterocyclyl-CH₂—,    -   or    -   R² denotes a group of formula (ii) including the pure        enantiomers and/or a mixture thereof

-   -   or    -   R² denotes, with the provisio that A¹ and A² denote N,        -   a group of formula (Iii),

-   -   wherein    -   W¹ and W² are independently selected from among a bond or        C₁₋₈-alkylene;    -   X¹ and X² are independently selected from among a 4- to        14-membered heterocyclic group;    -   Y¹ and Y² are independently selected from among a bond,        C₁₋₈-alkylene and —C₁₋₈-alkylamino-;    -   A³ is selected from the group consisting of a C₆₋₁₅-membered        aromatic carbocyclic group, —CONR⁵—(C₁₋₈-alkylene)-NR⁵CO—,        —CO—(C₁₋₈-alkylene)-CO—, —CO—(C₂₋₈-alkenylene)-CO—, —(CO)—,        —CO—(C₁₋₈-alkylene)-Z—(C₁₋₈-alkylene)-CO—,        —CO—(C₁₋₈-alkylene)-Z—CO—, —CO—Z—CO—,        —CO—NR⁵—(C₁₋₈-alkylene)-Z—(C₁₋₈-alkylene)-NR⁵—CO—,        —CO—NR⁵—(C₁₋₈-alkylene)-Z—NR⁵—CO—, —CO—NR⁵—Z—NR⁵—CO—,        C₃₋₁₅-carbocyclic group and a 4- to 14-membered heterocyclic        group;    -   Z is selected from among C₆₋₁₅-membered aromatic carbocyclic        group, C₃₋₁₅-carbocyclic group and a 4- to 14-membered        heterocyclic group;    -   R⁵ is hydrogen or C₁₋₈-alkyl;    -   R³ denotes hydrogen or methyl    -   or    -   R² and R³ together denote —CH₂—CH₂— or —CH₂—CH₂—CH₂—,    -   characterised in that the process comprises reaction steps (D)        and (F),    -   with the provisio that R² and R³ together must not denote        ethylene or propylene,    -   wherein    -   (D) is the reaction of a compound of formula (III) with a        compound of formula (VI)

-   -   wherein    -   R^(t) denotes C₁₋₄-alkyl;    -   R⁴ denotes a group selected from among C₁₋₄-alkylthio,        1-pyrazolyl, 1-imidazolyl and 1,2,4-triazol-1-yl, each        optionally substituted by one or two methyl groups,    -   to form a compound of formula (IV)

and

-   -   (F) is the reaction of a compound of formula (IV) with a        compound of formula (VII)

-   -   while steps (D) and (F) take place successively in the order        specified,    -   or    -   characterised in that the process comprises reaction step (E),        wherein    -   (E) is the reaction of a compound of formula (III) with a        compound of formula (VIII)

Preferred is a process for the preparation of a compound of formula (I)

-   -   optionally in the form of the tautomers thereof, and optionally        the acid addition salts thereof,    -   wherein the process comprises reaction steps (B), (D) and (F),        wherein    -   (B) is the reaction of a compound of formula (II)

-   -   wherein    -   X⁻ denotes a group selected from among PF₆ ⁻, BF₄ ⁻, SbF₆ ⁻,        phenylsulphonate, p-toluenesulphonate, HSO₄ ⁻, (SO₄ ²⁻)/2, FSO₃        ⁻ and F₃CSO₃ ⁻ and    -   R^(t) denotes C₁₋₄-alkyl    -   with a compound of formula (V)

R¹—COOH  (V)

-   -   in the presence of a base,    -   to form a compound of formula (III)

-   -   wherein    -   R^(t) denotes C₁₋₄-alkyl;    -   (D) is the reaction of a compound of formula (III) with a        compound of formula (VI)

-   -   wherein    -   R⁴ denotes a group selected from among C₁₋₄-alkylthio,        1-pyrazolyl, 1-imidazolyl and 1,2,4-triazol-1-yl, each        optionally substituted by one or two methyl groups    -   to form a compound of formula (IV)

-   -   and    -   (F) is the reaction of a compound of formula (IV) with a        compound of formula (VII)

-   -   while steps (B), (D) and (F) take place successively in the        order specified,    -   or    -   wherein the process comprises reaction steps (B) and (E),        wherein    -   (E) is the reaction of a compound of formula (III) with a        compound of formula (VIII)

-   -   while steps (B) and (E) take place successively in the order        specified.    -   or    -   wherein the process comprises reaction steps (C), (D) and (F),        wherein    -   (C) is the reaction of a tertiary alcohol selected from        tert-butanol, 2-methyl-2-butanol, 2-methyl-2-pentanol,        2-methyl-2-hexanol, 2,3-dimethyl-2-butanol and        2,4-dimethyl-2-pentanol;        -   and        -   5-methyl-1,2-oxazole        -   in the presence of an acid of formula XH        -   and a compound of formula (V) without isolation of a            compound of formula (II) to form a compound of formula (III)        -   wherein            -   XH denotes an acid selected from among HPF₆, HBF₄,                HSbF₆, phenylsulphonic acid, p-toluenesulphonic acid,                H₂SO₄, (H₂SO₄)/2, F₃CCOOH, FSO₃H, and F₃CSO₃H;            -   R^(t) denotes C₁₋₄-alkyl    -   or    -   wherein the process comprises reaction steps (C) and (E),    -   while steps (C) and (E) take place successively in the order        specified.

A further embodiment of the current invention is a process for thepreparation of compounds of general formula (III)

-   -   optionally in the form of the tautomers thereof, and optionally        the acid addition salts thereof,    -   characterised in that the process comprises reaction steps (B)        or (C),    -   wherein    -   (B) is the reaction of a compound of formula (II)

-   -   wherein    -   X⁻ denotes a group selected from among PF₆ ⁻, BF₄ ⁻, SbF₆ ⁻,        phenylsulphonate, p-toluenesulphonate, HSO₄ ⁻, (SO₄ ²⁻)/2, FSO₃        ⁻ and F₃CSO₃ ⁻;    -   R^(t) denotes C₁₋₄-alkyl; preferably methyl,    -   with a compound of formula (V)

R¹—COOH  (V)

-   -   in the presence of a base,    -   to form a compound of formula (III)

-   -   wherein    -   R¹ denotes a group of formula (i),

-   -   wherein    -   A¹ and A² independently from each other denote N or CH;    -   R^(1.1) denotes hydrogen or a group selected from among chloro,        bromo and methyl,    -   R^(1.2) denotes hydrogen or a group selected from among amino,        C₁₋₃-alkyl-NH—, (C₁₋₃-alkyl)₂N— and methyl,    -   or    -   R^(1.1) and R^(1.2) together form an annelated benzo ring;    -   R^(t) denotes C₁₋₄-alkyl;    -   and    -   (C) is the reaction of a tertiary alcohol selected from        tert-butanol, 2-methyl-2-butanol, 2-methyl-2-pentanol,        2-methyl-2-hexanol, 2,3-dimethyl-2-butanol and        2,4-dimethyl-2-pentanol;        -   and        -   5-methyl-1,2-oxazole        -   in the presence of an acid of formula XH        -   and a compound of formula (V) without isolation of a            compound of formula (II) to form a compound of formula (III)        -   wherein        -   XH denotes an acid selected from among HPF₆, HBF₄, HSbF₆,            phenylsulphonic acid, p-toluenesulphonic acid, H₂SO₄,            (H₂SO₄)/2, F₃CCOOH, FSO₃H and F₃CSO₃H;

Preferrably the process for the preparation of compounds of generalformula (III),

-   -   wherein    -   R^(t) denotes methyl or ethyl, particularly preferred ethyl,    -   comprises reaction step (C).

Preferrably the process for the preparation of compounds of generalformula (III),

-   -   optionally in the form of the tautomers thereof, and optionally        the acid addition salts thereof,    -   wherein    -   R¹ denotes a group of formula (i),

-   -   wherein    -   A¹ and A² independently from each other denote N or CH;    -   R^(1.1) denotes hydrogen or a group selected from among chloro,        bromo and methyl,    -   R^(1.2) denotes hydrogen or a group selected from among amino,        C₁₋₃-alkyl-NH—, (C₁₋₃-alkyl)₂N— and methyl;    -   R^(t) denotes C₁₋₄-alkyl;    -   comprises reaction steps (A) and (B),    -   wherein    -   (A) is the reaction of a tertiary alcohol selected from among        tert-butanol and 2-methyl-2-butanol, and 5-methyl-1,2-oxazole        with an acid of formula XH to form a compound of formula (II)

-   -   wherein    -   R^(t) denotes methyl or ethyl; preferably methyl,    -   X⁻ denotes a group selected from among PF₆ ⁻, BF₄ ⁻, SbF₆ ⁻,        phenylsulphonate, p-toluenesulphonate, HSO₄ ⁻, (SO₄ ²⁻)/2, FSO₃        ⁻, and F₃CSO₃ ⁻;    -   XH denotes the respective conjugate acid of X⁻;    -   while steps (A) and (B) take place successively in the order        specified.

The invention further relates to a process for the preparation ofcompounds of general formula (II),

-   -   wherein    -   R^(t) denotes C₁₋₄-alkyl;    -   X⁻ denotes a group selected from among PF₆ ⁻, BF₄ ⁻, SbF₆ ⁻,        phenylsulphonate, p-toluenesulphonate, HSO₄ ⁻, (SO₄ ²⁻)/2, FSO₃        ⁻, and F₃CSO₃ ⁻.    -   wherein the process comprises reaction step (A),    -   wherein    -   (A) is the reaction of a tertiary alcohol selected from among        tert-butanol, 2-methyl-2-butanol, 2-methyl-2-pentanol,        2-methyl-2-hexanol, 2,3-dimethyl-2-butanol and        2,4-dimethyl-2-pentanol        -   and 5-methyl-1,2-oxazole        -   with an acid of formula XH,        -   preferred is the reaction of tert-butanol or            2-methyl-2-butanol        -   and 5-methyl-1,2-oxazole        -   with an acid of formula XH,        -   wherein        -   XH denotes the respective conjugate acid of X⁻.

The invention further relates to a compound of formula (II),

-   -   wherein    -   X⁻ denotes a group selected from among an anion selected from        among PF₆ ⁻, BF₄ ⁻, SbF₆ ⁻, phenylsulphonate,        p-toluenesulphonate, HSO₄ ⁻, (SO₄ ²⁻)/2, FSO₃ ⁻ and F₃CSO₃ ⁻ and    -   R^(t) denotes C₁₋₄-alkyl.

Preferred is a compound wherein X⁻ denotes PF₆ ⁻ and R^(t) denotesmethyl.

The invention further relates to the use of a compound of formula (II)for the preparation of acylguanidines and acylthioureas, preferably forthe preparation of acylguanidines.

The invention further relates to the use of a compound of formula (II)for the preparation of carboxylic acid2-(2-methyl-C₁₋₆-alk-2-yl)carbamoyl-1-methyl-vinyl esters, preferablyfor the preparation of a compound of formula (III).

The invention further relates to a compound of formula (III.1)

-   -   wherein    -   A¹ and A² independently from each other denote N or CH;    -   R^(1.1) denotes hydrogen or a group selected from among chloro,        bromo and methyl,    -   R^(1.2) denotes hydrogen or a group selected from among amino,        C₁₋₃-alkyl-NH—, (C₁₋₃-alkyl)₂N— and methyl,    -   or    -   R^(1.1) and R^(1.2) together form an annelated benzo ring.

Preferred is a compound of formula (III.2)

-   The invention further relates to the use of a compound of formula    (III.2) for the preparation of a compound of formula (I.1)

-   -   wherein    -   R² denotes hydrogen or a group selected from among C₁₋₆-alkyl,        C₆₋₁₀-aryl-C₁₋₆-alkyl-, heterocyclyl and heterocyclyl-CH₂;    -   or    -   R² denotes a group of formula (ii) including the pure        enantiomers thereof

-   -   or    -   R² denotes a group of formula (iii)

-   -   wherein    -   W¹ and W² are independently selected from among a bond or        C₁₋₈-alkylene;    -   X¹ and X² are independently selected from among a 4- to        14-membered heterocyclic group;    -   Y¹ and Y² are independently selected from among a bond,        C₁₋₈-alkylene- or —C₁₋₈-alkylamino-;    -   A³ is selected from the group consisting of a C₆₋₁₅-membered        aromatic carbocyclic group, —CONR⁵—(C₁₋₈-alkylene)-NR⁵CO—,        —CO—(C₁₋₈-alkylene)-CO—, —CO—(C₂₋₈-alkenylene)-CO—, —(CO)—,        —CO—(C₁₋₈-alkylene)-Z—(C₁₋₈-alkylene)-CO—,        —CO—(C₁₋₈-alkylene)-Z—CO—, —CO—Z—CO—,        —CO—NR⁵—(C₁₋₈-alkylene)-Z—(C₁₋₈-alkylene)-NR⁵—CO—,        —CO—NR⁵—(C₁₋₈-alkylene)-Z—NR⁵—CO—, —CO—NR⁵—Z—NR⁵—CO—,        C₃₋₁₅-carbocyclic group and a 4- to 14-membered heterocyclic        group;    -   Z is selected from among C₆₋₁₅-membered aromatic carbocyclic        group, C₃₋₁₅-carbocyclic group and a 4- to 14-membered        heterocyclic group;    -   R⁵ is hydrogen or C₁₋₈-alkyl;    -   R³ denotes hydrogen or methyl    -   or    -   R² and R³ together denote —CH₂—CH₂— or —CH₂—CH₂—CH₂—.

TERMS AND DEFINITIONS USED

The compounds according to the invention unless otherwise specified maybe present in the form of the tautomers as well as in the form of thefree bases or the corresponding acid addition salts withpharmaceutically acceptable acids—such as for example acid additionsalts with hydrochloric acid, hydrobromic acid, sulphuric acid,methanesulphonic acid, phosphoric acid, fumaric acid, succinic acid,lactic acid, citric acid, tartaric acid, or maleic acid.

Terms not specifically defined herein should be given the meanings thatwould be given to them by one of skill in the art in light of thedisclosure and the context. As used in the specification, however,unless specified to the contrary, the following terms have the meaningindicated and the following conventions are adhered to.

In the groups, radicals, or moieties defined below, the number of carbonatoms is often specified preceding the group, for example, —C₁₋₆-alkylmeans an alkyl group or radical having 1 to 6 carbon atoms. In general,for groups comprising two or more subgroups, the last named group is theradical attachment point, for example, “thioalkyl” means a monovalentradical of the formula HS-Alk-. Unless otherwise specified below,conventional definitions of terms control and conventional stable atomvalences are presumed and achieved in all formulas and groups.

In general, all tautomeric forms and isomeric forms and mixtures,whether individual geometric isomers or optical isomers or racemic ornon-racemic mixtures of isomers, of a chemical structure or compound isintended, unless the specific stereochemistry or isomeric form isspecifically indicated in the compound name or structure.

The term “substituted” as used herein, means that any one or morehydrogens on the designated atom is replaced with a selection from theindicated group, provided that the designated atom's normal valence isnot exceeded, and that the substitution results in a stable compound.

By the term “optionally substituted” is meant within the scope of theinvention the above-mentioned group, optionally substituted by alower-molecular group. Examples of lower-molecular groups regarded aschemically meaningful are groups consisting of 1-200 atoms. Preferablysuch groups have no negative effect on the pharmacological efficacy ofthe compounds. For example the groups may comprise:

-   -   Straight-chain or branched carbon chains, optionally interrupted        by heteroatoms, optionally substituted by rings, heteroatoms or        other common functional groups.    -   Aromatic or non-aromatic ring systems consisting of carbon atoms        and optionally heteroatoms, which may in turn be substituted by        functional groups.    -   A number of aromatic or non-aromatic ring systems consisting of        carbon atoms and optionally heteroatoms which may be linked by        one or more carbon chains, optionally interrupted by        heteroatoms, optionally substituted by heteroatoms or other        common functional groups.

The term “pharmaceutically acceptable prodrug” as used herein means aprodrug of a compound of the invention which is, within the scope ofsound medical judgment, suitable for use in contact with the tissues ofhumans and lower animals without undue toxicity, irritation, allergicresponse, and the like, commensurate with a reasonable benefit/riskratio, and effective for their intended use, as well as the zwitterionicforms, where possible.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

As used herein, “pharmaceutically acceptable salts” refer to derivativesof the disclosed compounds wherein the parent compound is modified bymaking acid or base salts thereof. Examples of pharmaceuticallyacceptable salts include, but are not limited to, mineral or organicacid salts of basic residues such as amines; alkali or organic salts ofacidic residues such as carboxylic acids; and the like. Thepharmaceutically acceptable salts include the conventional non-toxicsalts or the quaternary ammonium salts of the parent compound formed,for example, from non-toxic inorganic or organic acids. For example,such conventional non-toxic salts include those derived from inorganicacids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric,nitric and the like; and the salts prepared from organic acids such asacetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric,citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic,benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric,toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isothionic,and the like. (also see Pharmaceutical salts, Birge, S. M. et al., J.Pharm. Sci., (1977), 66, 1-19). As the compounds of the presentinvention may have both, acid as well as basic groups, those compoundsmay therefore be present as internal salts too.

The pharmaceutically acceptable salts of the present invention can besynthesized from the parent compound which contains a basic or acidicmoiety by conventional chemical methods. Generally, such salts can beprepared by reacting the free acid or base forms of these compounds witha stoichiometric amount of the appropriate base or acid in water or inan organic solvent, or in a mixture of the two; generally, non-aqueousmedia like ether, ethyl acetate, ethanol, isopropanol, or acetonitrileare preferred.

The term “aryl” as used herein, either alone or in combination withanother substituent, means either an aromatic monocyclic system oraromatic multicyclic systems containing carbon atoms. For example, arylincludes a phenyl or a naphthyl ring system, wherein aryl meansgenerally an aromatic system, for example phenyl.

The term “heteroaryl” (heterocyclic aromatic groups) denotes five- orsix-membered heterocyclic aromatic groups or 5-10 membered, bicyclicheteroaryl rings which may contain one, two or three heteroatoms,selected from among oxygen, sulphur and nitrogen, which containsufficient conjugated double bonds that an aromatic system is formed.The ring may be linked to the molecule through a carbon atom or ifpresent through a nitrogen atom. The following are examples of five- orsix-membered heterocyclic aromatic groups:

Examples of 5-10-membered bicyclic heteroaryl rings include pyrrolizine,indole, indolizine, isoindole, indazole, purine, quinoline,isoquinoline, benzimidazole, benzofuran, benzopyrane, benzothiazole,benzoisothiazole, pyridopyrimidine, pteridine and pyrimidopyrimidine.

The term “annelated species of aryl or heteroaryl” as used herein,either alone or in combination with another substituent wherein theannelated species presents as a aryl-het (a), a het-aryl (b) or ahet-het (c) annelation means a monovalent substituent derived by removalof one hydrogen from

an aromatic monocyclic system or aromatic multicyclic systems containingcarbon atoms, which is annelated to a five-, six- or seven-memberedsaturated or unsaturated (including aromatic) heterocycle containingcarbon atoms and one, two, three or four ring heteroatoms selected fromnitrogen, oxygen and sulfur or

a five-, six-, or seven-membered saturated or unsaturated (includingaromatic) heterocycle containing carbon atoms and one, two, three orfour ring heteroatoms selected from nitrogen, oxygen and sulfur, whichis annelated to an aromatic monocyclic system or aromatic multicyclicsystems containing carbon atoms or

a five-, six-, or seven-membered saturated or unsaturated (includingaromatic) heterocycle containing carbon atoms and one, two, three orfour ring heteroatoms selected from nitrogen, oxygen and sulfur, whichis annelated to a five-, six-, or seven-membered saturated orunsaturated (including aromatic) heterocycle containing carbon atoms andone, two, three or four ring heteroatoms selected from nitrogen, oxygenand sulfur.

Suitable examples of an annelated species of aryl or het include:quinolinyl, 1-indoyl, 3-indoyl, 5-indoyl, 6-indoyl, indolizinyl,benzimidazyl or purinyl.

The term “halogen” as used herein means a halogen substituent selectedfrom fluoro, chloro, bromo or iodo.

By the term “C₁₋₆-alkyl” (including those which are part of othergroups) are meant branched and unbranched alkyl groups with 1 to 6carbon atoms, and by the term “C₁₋₄-alkyl” are meant branched andunbranched alkyl groups with 1 to 4 carbon atoms. Alkyl groups with 1 to4 carbon atoms are preferred. Examples of these include: methyl, ethyl,n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl,n-pentyl, iso-pentyl, neo-pentyl or hexyl. The abbreviations Me, Et,n-Pr, i-Pr, n-Bu, i-Bu, t-Bu, etc. may optionally also be used for theabove-mentioned groups. Unless stated otherwise, the definitions propyl,butyl, pentyl and hexyl include all the possible isomeric forms of thegroups in question. Thus, for example, propyl includes n-propyl andiso-propyl, butyl includes iso-butyl, sec-butyl and tert-butyl etc. Bythe term “C₁₋₆-alkylene” (including those which are part of othergroups) are meant branched and unbranched alkylene groups with 1 to 6carbon atoms and by the term “C₁₋₄-alkylene” are meant branched andunbranched alkylene groups with 1 to 4 carbon atoms. Alkylene groupswith 1 to 4 carbon atoms are preferred. Examples include: methylene,ethylene, propylene, 1-methylethylene, butylene, 1-methylpropylene,1,1-dimethylethylene, 1,2-dimethylethylene, pentylene,1,1-dimethylpropylene, 2,2-dimethylpropylene, 1,2-dimethylpropylene,1,3-dimethylpropylene or hexylene. Unless stated otherwise, thedefinitions propylene, butylene, pentylene and hexylene also include allthe possible isomeric forms of the relevant groups with the same numberof carbons. Thus for example propyl also includes 1-methylethylene andbutylene includes 1-methylpropylene, 1,1-dimethylethylene,1,2-dimethylethylene.

The term “C₂₋₆-alkenyl” (including those which are part of other groups)denotes branched and unbranched alkenyl groups with 2 to 6 carbon atomsand the term “C₂₋₄-alkenyl” denotes branched and unbranched alkenylgroups with 2 to 4 carbon atoms, provided that they have at least onedouble bond. Preferred are alkenyl groups with 2 to 4 carbon atoms.Examples include: ethenyl or vinyl, propenyl, butenyl, pentenyl, orhexenyl. Unless otherwise stated, the definitions propenyl, butenyl,pentenyl and hexenyl include all possible isomeric forms of the groupsin question. Thus, for example, propenyl includes 1-propenyl and2-propenyl, butenyl includes 1-, 2- and 3-butenyl, 1-methyl-1-propenyl,1-methyl-2-propenyl etc.

By the term “C₂₋₆-alkenylene” (including those which are part of othergroups) are meant branched and unbranched alkenylene groups with 2 to 6carbon atoms and by the term “C₂₋₄-alkenylene” are meant branched andunbranched alkylene groups with 2 to 4 carbon atoms. Alkenylene groupswith 2 to 4 carbon atoms are preferred. Examples include: ethenylene,propenylene, 1-methylethenylene, butenylene, 1-methylpropenylene,1,1-dimethylethenylene, 1,2-dimethylethenylene, pentenylene,1,1-dimethylpropenylene, 2,2-dimethylpropenylene,1,2-dimethylpropenylene, 1,3-dimethylpropenylene or hexenylene. Unlessstated otherwise, the definitions propenylene, butenylene, pentenyleneand hexenylene include all the possible isomeric forms of the respectivegroups with the same number of carbons. Thus, for example, propenyl alsoincludes 1-methylethenylene and butenylene includes 1-methylpropenylene,1,1-dimethylethenylene, 1,2-dimethylethenylene.

By the term “C₂₋₆-alkynyl” (including those which are part of othergroups) are meant branched and unbranched alkynyl groups with 2 to 6carbon atoms and by the term “C₂₋₄-alkynyl” are meant branched andunbranched alkynyl groups with 2 to 4 carbon atoms, provided that theyhave at least one triple bond. Alkynyl groups with 2 to 4 carbon atomsare preferred. Examples include: ethynyl, propynyl, butynyl, pentynyl,or hexynyl. Unless stated otherwise, the definitions propynyl, butynyl,pentynyl and hexynyl include all the possible isomeric forms of therespective groups. Thus, for example, propynyl includes 1-propynyl and2-propynyl, butynyl includes 1-, 2- and 3-butynyl, 1-methyl-1-propynyl,1-methyl-2-propynyl etc.

By the term “C₂₋₆-alkynylene” (including those which are part of othergroups) are meant branched and unbranched alkynylene groups with 2 to 6carbon atoms and by the term “C₂₋₄-alkynylene” are meant branched andunbranched alkylene groups with 2 to 4 carbon atoms. Alkynylene groupswith 2 to 4 carbon atoms are preferred. Examples include: ethynylene,propynylene, 1-methylethynylene, butynylene, 1-methylpropynylene,1,1-dimethylethynylene, 1,2-dimethylethynylene, pentynylene,1,1-dimethylpropynylene, 2,2-dimethylpropynylene,1,2-dimethylpropynylene, 1,3-dimethylpropynylene or hexynylene. Unlessstated otherwise, the definitions propynylene, butynylene, pentynyleneand hexynylene include all the possible isomeric forms of the respectivegroups with the same number of carbons. Thus for example propynyl alsoincludes 1-methylethynylene and butynylene includes 1-methylpropynylene,1,1-dimethylethynylene, 1,2-dimethylethynylene. By the term“C₁₋₆-alkoxy” (including those which are part of other groups) are meantbranched and unbranched alkoxy groups with 1 to 6 carbon atoms and bythe term “C₁₋₄-alkoxy” are meant branched and unbranched alkoxy groupswith 1 to 4 carbon atoms. Alkoxy groups with 1 to 4 carbon atoms arepreferred. Examples include: methoxy, ethoxy, propoxy, butoxy orpentoxy. The abbreviations OMe, OEt, OPr, etc. may optionally be usedfor the above-mentioned groups. Unless stated otherwise, the definitionspropoxy, butoxy and pentoxy include all the possible isomeric forms ofthe respective groups. Thus for example propoxy includes n-propoxy andiso-propoxy, butoxy includes iso-butoxy, sec-butoxy and tert-butoxy etc.

The term “C₃₋₈-cycloalkyl” (including those which are part of othergroups) as used herein means cyclic alkyl groups with 3 to 8 carbonatoms, preferred are cyclic alkyl groups with 5 to 6 carbon atoms.Examples include: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl or cyclooctyl.

By the term “C₃₋₆-cycloalkenyl” (including those which are part of othergroups) is a cyclic alkyl group meant with 5 or 6 carbon atoms whichcontain one or two double bonds. Examples include: cyclopentenyl,cyclopentadienyl, cyclohexenyl or cyclohexadienyl. By the term“C₁₋₆-haloalkyl” (including those which are part of other groups) aremeant branched and unbranched alkyl groups with 1 to 6 carbon atomswherein one or more hydrogen atoms are replaced by a halogen atomselected from among fluorine, chlorine or bromine, preferably fluorineand chlorine, particularly preferably fluorine. By the term“C₁₋₄-haloalkyl” are meant correspondingly branched and unbranched alkylgroups with 1 to 4 carbon atoms, wherein one or more hydrogen atoms arereplaced analogously to what was stated above. C₁₋₄-haloalkyl ispreferred. Examples include: CH₂F, CHF₂, CF₃,

Where a hyphen open on one side “-” is used in the structural formula ofa substituent, this hyphen is to be understood as the linkage point tothe remainder of the molecule. The substituent replaces thecorresponding groups R¹, R², etc. If no hyphen open on one side is usedin the structural formula of a substituent, the linkage point to theremainder of the molecule is clear from the structural formula itself.

Where a star “*” is used in the structural formula of a substituent,this star is to be understood as the linkage point to the remainder ofthe molecule. The substituent replaces the corresponding groups R¹, R²,etc. If there are two stars used in the structural formula of asubstituent the substituent is linked with two molecules.

The substituent R¹ denotes a group of formula (i),

wherein

-   A¹ and A² independently from each other denote N or CH, preferably    N;-   R^(1.1) denotes hydrogen or a group selected from among chloro,    bromo and methyl, preferably chloro.-   R^(1.2) denotes hydrogen or a group selected from among amino,    (C₁₋₃-alkyl)₂N— and methyl, preferably amino.-   or-   R^(1.1) and R^(1.2) together form an annelated benzo ring;

The substituent R² denotes hydrogen or a group selected from amongC₁₋₆-alkyl, C₆₋₁₀-aryl-C₁₋₆-alkyl-, heterocyclyl, heterocyclyl-CH₂—, —,preferably benzyl,

more preferably R² denotes a group of formula (ii)

-   -   including the pure enantiomers thereof,    -   or also preferred    -   R² denotes, with the provisio that A¹ and A² denote N, a group        of formula (iii)

-   -   wherein    -   W¹ and W² are independently selected from among a bond or        C₁₋₈-alkylene;    -   X¹ and X² are independently selected from among a 4- to        14-membered heterocyclic group;    -   Y¹ and Y² are independently selected from among a bond,        C₁₋₈-alkylene- or C₁₋₈-alkylamino-;    -   A³ is selected from the group consisting of a C₆₋₁₅-membered        aromatic carbocyclic group, —CONR⁵—(C₁₋₈-alkylene)-NR⁵CO—,        —CO—(C₁₋₈-alkylene)-CO—, —CO—(C₂₋₈-alkenylene)-CO—,        —CO—(C₁₋₈-alkylene)-Z—(C₁₋₈-alkylene)-CO—,        —CO—(C₁₋₈-alkylene)-Z—CO—,        —CO—NR⁵—(C₁₋₈-alkylene)-Z—(C₁₋₈-alkylene)-NR⁵—CO—,        —CO—NR⁵—(C₁₋₈-alkylene)-Z—NR⁵—CO—, —CO—NR⁵—Z—NR⁵—CO—,        C₃₋₁₅-carbocyclic group and a 4- to 14-membered heterocyclic        group;    -   Z is selected from among C₆₋₁₅-membered aromatic carbocyclic        group, C₃₋₁₅-carbocyclic group and a 4- to 14-membered        heterocyclic group;    -   R⁵ is hydrogen or C₁₋₈-alkyl;    -   R³ denotes a hydrogen or methyl, preferably hydrogen    -   or    -   R² and R³ together denote —CH₂—CH₂— or —CH₂—CH₂—CH₂—,

The substituent R⁴ may denote a group selected from among alkylthio,1-pyrazolyl, 1-imidazolyl and 1,2,4-triazol-1-yl, each optionallysubstituted by one or two methyl groups, preferably 1-pyrazolyl.

The substituent R^(t) denotes a group selected from among C₁₋₄-alkyl,preferably methyl or ethyl.

X⁻ denotes a group selected from among PF₆ ⁻, BF₄ ⁻, SbF₆ ⁻,phenylsulphonate, p-toluenesulphonate, HSO₄ ⁻, (SO₄ ²⁻)/2, FSO₃ ⁻ andF₃CSO₃ ⁻; preferably PF₆ ⁻ and F₃CSO₃ ⁻.

Process step (A) is preferably carried out neat or in a solvent selectedfrom among water, methanol, ethanol, tetrahydrofuran (THF),diethylether, tert-butyl-methylether, dimethylformamide (DMF),N-methyl-2-pyrrolidone (NMP), N-ethyl-2-pyrrolidone (NEP) anddimethylsulphoxide (DMSO), or mixtures thereof, preferably in a mixturecontaining water and tetrahydrofuran (THF) and/or diethylether.Especially preferred is that all or part of the solvents used are addednot from the beginning but after the addition of the acid XH in order toachieve precipitation of the compound (II) formed during the process.

Process step (A) is carried out in a temperature range of from −20° C.to 40° C., preferably from 0° C. to 25° C.

Process step (B) is preferably carried out in the presence of a baseselected from among triethylamine, di-isopropyl-ethylamine andN-methylmorpholine, preferably triethylamine.

Process step (B) is preferably carried out in a solvent selected fromamong DMF, NMP, NEP and DMSO, preferably in DMF.

Process step (B) is preferably carried out at an initial temperatureranging from 20° C. to 60° C., particularly preferably from 20° C. to50° C. Preferably, the temperature is allowed to lower during theprocess, most preferably to ambient temperature. The skilled person willappreciate that depending on R¹, the addition of water at a latertimepoint during the process may promote precipitation of the compoundof formula (III) formed during the process. The final temperature whenseparating the product is preferably −20° C. to 25° C., most preferably0° C. to 20° C.

Process step (C) is preferably carried out with the addition of a baseselected from among triethylamine, di-isopropyl-ethylamine andN-methylmorpholine, preferably triethylamine.

Process step (C) is preferably carried out neat or applying a solventselected from among DMF, NMP, NEP and DMSO, preferably DMF.

Stage 1 of process step (C) is preferably carried out in a temperaturerange of from 0° C. to 30° C., preferably from 0° C. to 20° C.,particularly preferable at a temperature from 0° C. to 5° C. The skilledperson will appreciate that depending on R¹, the addition of water at alater timepoint during the process may promote precipitation of thecompound of formula (III) formed during the process. The finaltemperature when separating the product is preferably 0° C. to 25° C.,most preferably 0° C. to 20° C.

Process step (D) is preferably carried out applying a base selected fromamong sodium hydroxide, sodium carbonate, sodium bicarbonate, potassiumhydroxide, potassium carbonate, potassium tert-butylate, sodiummethanolate and sodium ethanolate, preferably sodium hydroxide andpotassium tert-butylate.

Process step (D) is preferably carried out applying a solvent selectedfrom among tert-butylmethyl ether (TBME), tetrahydrofuran (THF),dichlormethane (DCM), acetonitrile, diethylether, dimethylformamide(DMF), N-methyl-2-pyrrolidone (NMP), N-ethyl-2-pyrrolidone (NEP) anddimethylsulphoxide (DMSO), or mixtures thereof, preferably TBME, THF andDCM, or a mixture thereof, particularly preferable TBME and THF or amixture thereof.

Process step (D) is preferably carried out in a temperature range offrom 15° C. to the boiling point of the solvent applied. With theproviso that R⁴ denotes alkylthio, process step (D) is most preferablycarried out at a temperature from 15 to 25° C.

The skilled person will appreciate that depending on R³ and R⁴, theaddition of water at a later timepoint during the process may promoteprecipitation of the compound of formula (IV) formed during the process.

Process step (E) is preferably carried out in the presence of a baseselected from among sodium hydroxide, sodium carbonate, potassiumhydroxide, potassium carbonate, sodium methanolate, sodium ethanolateand potassium tert-butanolate. Also preferred is the process step (E)carried out in the presence of an alcoholate generated by addition ofsodium or sodium hydride to a solvent selected from methanol, ethanol,2-propanol and tert-butanol. Most preferably, the process step iscarried out in the presence of a base selected from among sodiumhydroxide, potassium hydroxide, sodium ethanolate, sodium 2-propanolate,sodium tert-butanolate and potassium tert-butanolate which in the caseof sodium alcoholates may be generated by addition of metallic sodium orsodium hydride to the respective alcohol.

In process step (E) formula (VIII) is preferably used as a free base oras an acid addition salt, preferably as an acid addition salt selectedfrom among hydrochloric acid, hydrobromic acid, sulphuric acid,methylsulphonic acid and p-tolylsulphonic acid.

Process step (E) is preferably carried out in a solvent selected fromamong tetrahydrofuran (THF), dioxane, methanol, ethanol, 2-propanol andtert-butanol or a mixture thereof, most preferably in ethanol and2-propanol.

Process step (E) is preferably carried out in a temperature range offrom 40° C. to 90° C., preferably from 50° C. to 85° C.

Process step (F) is preferably carried out in the presence of a baseselected from among triethylamine di-isopropyl-ethylamine andN-methylmorpholine, preferably triethylamine.

Process step (F) is preferably carried out in a solvent selected fromamong methanol, ethanol, 2-propanol, acetonitrile, DCM, tetrahydrofuran(THF), diethylether, dimethylformamide (DMF), N-methyl-2-pyrrolidone(NMP), N-ethyl-2-pyrrolidone (NEP) and dimethylsulphoxide (DMSO), ormixtures thereof, preferably selected from among methanol, ethanol, DMFand THF or mixtures thereof, most preferably in ethanol and DMF.

Process step (F) is preferably carried out in a temperature range offrom 50° C. to 90° C., preferably from 65° C. to 80° C.

Scheme 1 illustrates the synthesis according to the invention.

The following examples serve to illustrate the process for preparing thecompounds of formula (I) carried out by way of example. These examplesare to be taken as an illustration of the invention without restrictingthe latter to its subject-matter.

Preparation of the Compounds According to Scheme 1 Example 12-tert-Butyl-5-methyl-1,2-oxazol-2-ium; hexafluoro-phosphate

Process Step (A)

To an ice-cold mixture of tert-butanol (11.4 g; 154 mmol) and5-methylisoxazole (12.5 ml; 154 mmol) kept under nitrogen atmosphere isadded dropwise with cooling (ice-bath) hexafluorophosphoric acid (60% inwater; 22.7 ml; 154 mmol). The ice-bath is removed and the resultingmixture is stirred at r.t. for further 2 h. To the stirred mixture, THF(10 ml) and diethyl ether (40 ml) is added. After further stirring for10 min, the precipitate formed is filtered off with suction, washed withdiethyl ether and dried in vacuo (C₈H₁₄NO×F₆P).

Yield: 19.6 g (45% of theory)

ESI Mass spectrum: m/z=140 [M]⁺

IR (KBr): =3159 (m), 1597 (s), 1513 (ss), 1381 (s), 1245 (s), 1212 (ss),1053 (s), 1036 (s), 1008 (s), 813 (ss)

¹H-NMR (400 MHz, DMSO): δ=1.69 (s, 9H); 2.69 (s, 3H); 7.19 (s, 1H); 9.69(s, 1H)

Melting point: 107-108° C.

Differential Scanning Calorimetry data (Closed gold vessel):

Exothermic event of ΔH=656 J/g and T_(onset)=193° C.

For comparison:

Differential Scanning calorimetry data (Closed gold vessel) for2-tert-butyl-5-methyl-1,2-oxazol-2-ium perchlorate (“Woodward's reagentL”):

Exothermic event of ΔH=4395 J/g and T_(onset)=158° C.

Example 2 1-(tert-Butylcarbamoyl)prop-1-en-2-yl3,5-diamino-6-chloropyrazine-2-carboxylate

Alternative 1 Via Process Step (B)

3,5-Diamino-6-chloropyrazine-2-carboxylic acid (2.00 g; 10.6 mmol) inabs. DMF (20.0 ml) is warmed to approx. 40-50° C. to achieve completesolution. 2-tert-butyl-5-methyl-1,2-oxazol-2-ium hexafluoro-phosphate(6.05 g; 21.2 mmol) and triethylamine (2.94 ml; 21.2 mmol) are added andthe resulting mixture is stirred at r.t. over night. Ice-water is addedand the precipitate formed is filtered off with suction, washed withwater and dried in vacuo at 65° C. to yield the title compound(C₁₃H₁₈ClN₅O₃).

Yield: 2.76 g (79% of theory)

ESI Mass spectrum: m/z=328 [M+H]⁺; m/z=326 [M−H]⁻

Alternative 2 Via Process Step (C)

Stage 1:

A mixture of tert-butanol (21.0 ml; 226 mmol) and 5-methylisoxazole(18.0 ml; 221 mmol) is cooled with an ice-bath.Trifluoromethanesulphonic acid (20.0 ml; 221 mmol) is added dropwisewith continued cooling. The resulting mixture is stirred for 1 h withoutfurther cooling.

Stage 2:

To a solution or suspension of 3,5-diamino-6-chloropyrazine-2-carboxylicacid (14.0 g; 74.2 mmol) and triethylamine (31.0 ml; 222 mmol) in DMF(1400 ml) is added the mixture prepared in stage 1. The resultingmixture is stirred for 4 h at r.t. Ice-water is added with stirring. Theprecipitate formed is filtered off with suction, washed with water anddried at 65° C. to yield the title compound (C₁₃H₁₈ClN₅O₃).

Yield: 18.2 g (75% of theory)

TLC (Silica; DCM/MeOH 9:1): R_(f)=0.4

ESI Mass spectrum: m/z=328 [M+H]⁺; m/z=326 [M−H]⁻

Example 3 1-(tert-Butylcarbamoyl)prop-1-en-2-yl3-amino-6-chloropyrazine-2-carboxylate

Process Step (B)

To a mixture of 3-amino-6-chloropyrazine-2-carboxylic acid (1.00 g; 5.76mmol) and triethylamine (2.40 ml; 17.3 mmol) in abs. DMF is added2-tert-butyl-5-methyl-1,2-oxazol-2-ium hexafluoro-phosphate (4.93 g;17.3 mmol). The mixture is stirred at r.t. over night. Ice-water isadded. The supernatant is decanted from the resin-like product which issufficiently pure to be further reacted

(C₁₃H₁₇ClN₄O₃)

ESI Mass spectrum: m/z=313 [M+H]⁺

Example 4 1-(tert-Butylcarbamoyl)prop-1-en-2-yl3-aminoquinoxaline-2-carboxylate

Process Step (C)

Stage 1:

A mixture of tert-butanol (7.06 g; 95.2 mmol) and 5-methylisoxazole(7.75 ml; 95.2 mmol) is cooled with an ice-bath.Trifluoromethanesulphonic acid (8.62 ml; 95.2 mmol) is added dropwisewith continued cooling. The resulting mixture is stirred for 1 h withoutfurther cooling.

Stage 2:

A solution of 3-aminoquinoxaline-2-carboxylic acid (6.00 g; 31.7 mmol)in DMF (50.0 ml) and triethylamine (13.3 ml; 95.2 mmol) is added to themixture prepared in stage 1 while cooling. The cooling bath is removedand the resulting mixture is stirred over night. Ice-water is added withstirring. The precipitate formed is filtered off with suction, washedwith water and dried at 65° C. to yield the title compound (C₁₇H₂₀N₄O₃).

Yield: 10.2 g (98% of theory)

IR: 1715 cm⁻¹ (C═O ester); 1647 cm⁻¹ (C═O amide)

ESI Mass spectrum: m/z=329 [M+H]⁺

Example 5 1-(tert-Butylcarbamoyl)prop-1-en-2-yl3-amino-6-chloro-5-[(cyclopropylmethyl)amino]pyrazine-2-carboxylate

Process Step (C)

Stage 1:

A mixture of tert-butanol (1.38 g; 18.5 mmol) and 5-methylisoxazole(1.51 ml; 18.5 mmol) is cooled with an ice-bath.Trifluoromethanesulphonic acid (1.68 ml; 1.85 mmol) is added dropwisewith continued cooling. The resulting mixture is stirred for 1 h withoutfurther cooling.

Stage 2:

A solution of3-amino-6-chloro-5-[(cyclopropylmethyl)amino]pyrazine-2-carboxylic acid(Prepared from the respective methyl ester by refluxing in aq. NaOH [J.Med. Chem. 10 (1967) 66-74]; 1.50 g; 6.18 mmol) in DMF (10.0 ml) andtriethylamine (2.59 ml; 18.5 mmol) is added to the mixture prepared instage 1 while cooling. The cooling bath is removed and the resultingmixture is stirred over night. Ice-water is added with stirring. Theprecipitate formed is filtered off with suction, washed with water anddried at 65° C. to yield the title compound (C₁₇H₂₄ClN₅O₃).

Yield: 2.31 g (98% of theory)

ESI Mass spectrum: m/z=382 [M+H]⁺

Example 6 1-(2-Methyl-2-butyl-carbamoyl)prop-1-en-2-yl3,5-diamino-6-chloropyrazine-2-carboxylate

Process Step (C)

Stage 1:

A mixture of 2-methyl-2-butanol (60.0 ml; 98%; 537 mmol) and5-methylisoxazole (46.0 ml; 95%; 536 mmol) is cooled with an ice-bath.Trifluoromethanesulphonic acid (51.0 ml; 98%; 565 mmol) is addeddropwise while stirring with continued cooling. The resulting mixture isstirred for 1 h, then over night without further cooling.

Stage 2:

To 3,5-diamino-6-chloropyrazine-2-carboxylic acid (42.3 g; 224 mmol) inDMF (338 ml) is added dropwise triethylamine (78.0 ml; 560 mmol) whilecooling with an ice-bath. To the resulting mixture is added dropwisewhile cooling with an ice-bath the mixture generated as described in“stage 1”. The temperature is thereby kept below 25° C. The mixture isstirred for further 2 hours without cooling and then poured intoice-water (1436 ml). The resulting suspension is stirred for 2 hours atambient temperature. The precipitate is filtered off with suction, takenup in THF/water (1:4; 75 ml), filtered again with suction and washedwith water. The product is dried in vacuo at 60° C. (C₁₄H₂₀ClN₅O₃).

Yield: 75.1 g (98% of theory)

TLC: R_(f)=0.30 (Silica; DCM/MeOH/HOAc=20:1:0.1)

ESI Mass spectrum: m/z=342 [M+H]⁺; m/z=340 [M−H]⁻

¹H-NMR (400 MHz, DMSO): δ=0.69 (t, 3H, J=7.4 Hz); 1.13 (s, 6H); 1.57(quart., 2H, J=7.4 Hz); 1.97 (s, 3H); 5.62 (s, 1H); 7.00 (s, 1H); 7.15(sb, 2H); 7.40 (sb)

Example 73,5-Diamino-6-chloro-N-[(methylsulfanyl)methanimidoyl]pyrazine-2-carboxamide

Process Step (D)

To NaOH (1 mol/l in water; 9.2 ml; 9.2 mmol) is addedS-methylisothiourea sulphate (1.78 g; 6.1 mmol). The mixture is stirreduntil complete solution is achieved. TBME/THF (1:1; 30 ml) and then1-(tert-butylcarbamoyl)prop-1-en-2-yl3,5-diamino-6-chloropyrazine-2-carboxylate (example 2) (2.00 g; 6.10mmol) are added and the mixture is stirred at r.t. over night, thenwater (6 ml) is added. The precipitate formed is filtered off withsuction, washed successively with water, methanol and then with diethylether and then dried at 50° C. (C₇H₉ClN₆OS).

Yield: 1.33 g (84% of theory)

ESI Mass spectrum: m/z=261 [M+H]⁺; m/z=259 [M−H]⁻

Example 83-amino-N-[(methylsulfanyl)methanimidoyl]quinoxaline-2-carboxamide

Process Step (D)

To NaOH (1 mol/l in water; 45.7 ml; 45.7 mmol) is addedS-methylisothiourea sulphate (10.6 g; 38.1 mmol). The mixture is stirreduntil complete solution is achieved. The resulting solution is added toa suspension of 1-(tert-butylcarbamoyl)prop-1-en-2-yl3-aminoquinoxaline-2-carboxylate (example 4) (5.00 g; 15.2 mmol) in THF(80 ml). The mixture is stirred at r.t. for 3 h, then volatiles areevaporated. Ice-water (100 ml) is added. The precipitate formed isfiltered off with suction, washed with water and then dried at 50° C.(C₁₁H₁₁N₅OS).

Yield: 2.95 g (74% of theory)

ESI Mass spectrum: m/z=262 [M+H]⁺

HPLC analytics: RT=1.18 min (HPLC method 1)

Example 93-Amino-5-cyclopropylmethylamino-6-chloro-N-[(methylsulfanyl)methanimidoyl]pyrazine-2-carboxamide

Process Step (D)

To NaOH (2 mol/l in water; 9.07 ml; 18.1 mmol) is addedS-methylisothiourea sulphate (5.05 g; 18.1 mmol). The mixture is stirreduntil complete solution is achieved. The resulting solution is added to1-(tert-butylcarbamoyl)prop-1-en-2-yl3-amino-6-chloro-5-[(cyclopropylmethyl)amino]pyrazine-2-carboxylate(example 5) (2.31 g; 6.05 mmol) in THF (50 ml). The mixture is stirredat r.t. for 3 d, then volatiles are evaporated. The residue is purifiedby RP-HPLC (modifier: trifluoro acetic acid (TFA) (C₁₁H₁₅ClN₆OS).

Yield: 178 mg (9% of theory)

ESI Mass spectrum: m/z=315 [M+H]⁺

Example 103,5-Diamino-6-chloro-N-[(1H-pyrazol-1-yl)methanimidoyl]pyrazine-2-carboxamide

Process Step (D)

To a mixture of 1H-pyrazole-1-carboxamidine hydrochloride (238 mg; 99%;1.61 mmol) and THF (2.0 ml) is added KOtBu (20% in THF; 1.00 ml; 1.61mmol). A mixture of 1-(2-methyl-2-butylcarbamoyl)prop-1-en-2-yl3,5-diamino-6-chloropyrazine-2-carboxylate (example 6) and THF (1.0 ml)is added with stirring. The mixture is refluxed over night, then allowedto cool to r.t. Water (6.0 ml) is added and the resulting suspension isstirred for 1 hour. The precipitate is filtered off with suction andwashed successively with THF/water (1:2; 3 ml) and THF/water (1:3; 2.0ml) (C₉H₉ClN₈O).

Yield: 260 mg (63% of theory)

TLC: R_(f)=0.45 (Silica; DCM/MeOH/aq. NH₃=9:1:0.1)

ESI Mass spectrum: m/z=281 [M+H]⁺; m/z=279 [M−H]⁻

¹H-NMR (400 MHz, DMSO+DCI): δ=6.96 (dd, J=3.0 Hz, J′=1.6 Hz, 1H); 8.28(d, J=1.6 Hz, 1H); 9.26 (d, J=3.0 Hz, 1H)

Example 113,5-Diamino-N-[(1E)-amino(benzylamino)methylidene]-6-chloropyrazine-2-carboxamide

Process Step (E)

A mixture of benzylguanidine hydrochloride (113 mg; 610 μmol) andpotassium tert-butylate (68 mg; 610 μmol) in dioxane (10 ml) is stirredat 50° C. for 30 min. 1-(tert-Butylcarbamoyl)prop-1-en-2-yl3,5-diamino-6-chloropyrazine-2-carboxylate (example 2) (200 mg; 610μmol) is added and the mixture is refluxed over night. Volatiles areevaporated and the residue is taken up in DMF. Insolubles are removed byfiltration and the resulting solution is evaporated to dryness. Theresidue is purified by RP-HPLC (modifier: TFA) to yield the titlecompound as a TFA salt (C₁₃H₁₄ClN₇O×n TFA).

ESI Mass spectrum: m/z=320 [M+H]⁺

Example 123,5-Diamino-6-chloro-N-(4,5-dihydro-1H-imidazol-2-yl)pyrazine-2-carboxamide

Process Step (E)

A mixture of 4,5-dihydro-1H-imidazol-2-ylamine tosylate (1.69 g; 6.57mmol) and sodium (119 mg; 5.19 mmol) in 2-propanol (20 ml) is refluxedfor 30 min. 1-(tert-Butylcarbamoyl)prop-1-en-2-yl3,5-diamino-6-chloropyrazine-2-carboxylate (example 2) (0.900 g; 2.75mmol) is added and the mixture is refluxed for further 60 min. Theprecipitate formed is filtered off with suction, suspended in water,filtered off again and dried at 50° C. to yield the title compound(C₈H₁₀ClN₇O).

Yield: 296 mg (42% of theory)

ESI Mass spectrum: m/z=256 [M+H]⁺: m/z=254 [M−H]⁻

HPLC analytics: RT=0.66 min (HPLC method 2)

Example 133,5-Diamino-N-[(1E)-amino({4-[4-(2,3-dihydroxypropoxy)phenyl]butyl}amino)methylidene]-6-chloropyrazine-2-carboxamide

Process Step (F)

To a mixture of 3-[4-(4-aminobutyl)-phenoxy]propane-1,2-diol (preparedas described in J. Med. Chem. 49 (2006) 4098-4115; 530 mg; 2.22 mmol)and ethanol (2.0 ml) in THF (10.0 ml) are added triethylamine (1.23 ml;8.86 mmol) and3,5-diamino-6-chloro-N-[(methylsulfanyl)methanimidoyl]pyrazine-2-carboxamide(example 7; 577 mg; 2.22 mmol). The mixture is stirred at 70° C. overnight, then volatiles are evaporated. The residue is purified by silicagel column chromatography (gradient: DCM/(Methanol/aq. ammonia 9:1)95:5→70:30) to yield the title compound (C₁₉H₂₆ClN₇O₄).

Yield: 260 mg (26% of theory)

TLC (Silica; DCM/MeOH/aq. ammonia 70:30:1): R_(f)=0.3

ESI Mass spectrum: m/z=452 [M+H]⁺; m/z=450 [M−H]⁻

HPLC analytics: RT=1.40 min (HPLC method 1)

Example 143,5-Diamino-N-[(1E)-amino(benzylamino)methylidene]-6-chloropyrazine-2-carboxamide

Process Step (F)

A mixture of3,5-diamino-6-chloro-N-[(1H-pyrazol-1-yl)methanimidoyl]pyrazine-2-carboxamide(example 10) (250 mg; 0.891 mmol), benzylamine (0.120 ml; 1.10 mmol) andDMF (2.0 ml) is stirred at 70° C. for 6 h, then over night at r.t.Tert-butyl methyl ether (4.0 ml) is added and the mixture is stirred forfurther 2 hours. The precipitate is filtered off with suction, washedwith tert-butyl methyl ether (4.0 ml) and dried in vacuo at 60° C.(C₁₃H₄ClN₇O).

Yield: 250 mg (73% of theory)

TLC: R_(f)=0.23 (Silica; DCM/MeOH/aq. NH₃=9:1:0.1)

ESI Mass spectrum: m/z=320 [M+H]⁺; m/z=318 [M−H]⁻

Example 151-(2-Methyl-2-butyl-carbamoyl)prop-1-en-2-yl-2-amino-5-bromobenzoate

Process Step (C)

Stage 1:

A mixture of 2-methyl-2-butanol (1.34 ml; 98%; 12.0 mmol) and5-methylisoxazole (1.03 ml; 95%; 12.0 mmol) is cooled with an ice-bath.Trifluoromethanesulphonic acid (1.13 ml; 98%; 12.5 mmol) is addeddropwise while stirring with continued cooling. The resulting mixture isstirred for 1 h, then over night without further cooling.

Stage 2:

To 2-amino-5-bromobenzoic acid (1.08 g; 5.00 mmol) in DMF (10 ml) isadded dropwise triethylamine (1.81 ml; 13.0 mmol) while cooling with anice-bath. To the resulting mixture is added dropwise while cooling withan ice-bath the mixture generated as described in “stage 1”. Thetemperature is thereby kept below 25° C. The mixture is stirred for 3days without cooling and then ice-water (30 ml) is added with vigorousstirring. The aqueous layer is decanted, additional ice-water and DCMare added. The organic layer is separated and evaporated. The residue ispurified by silica gel column chromatography (gradient: DCM/methanol100:0→93:7) to yield the title compound (C₁₆H₂₁BrN₂O₃).

Yield: 880 mg (48% of theory).

ESI Mass spectrum: m/z=369 [M+H]⁺; m/z=367 [M−H]⁻

HPLC analytics: RT=0.98 min (HPLC method 3)

Example 16 2-Amino-5-bromo-N-(4,5-dihydro-1H-imidazol-2-yl)benzamide

Process Step (E)

A mixture of 4,5-dihydro-1H-imidazol-2-ylamine tosylate (0.523 g; 2.03mmol) and sodium (37 mg; 1.63 mmol) in 2-propanol (16 ml) is refluxedfor 30 min.1-(tert-Butylcarbamoyl)-prop-1-en-2-yl-2-amino-5-bromobenzoate (example15) (0.300 g; 0.812 mmol) is added and the mixture is refluxed overnight. The precipitate formed is filtered off and discarded. Thefiltrate is evaporated, and the residue is purified by preparativeRP-HPLC (column: Xbridge C18 (Waters); water-ACN; modifier: ammonia) toyield the title compound (C₁₀H₁₁BrN₄O).

Yield: 96 mg (42% of theory)

ESI Mass spectrum: m/z=283 [M+H]⁺: m/z=281 [M−H]⁻

HPLC analytics: RT=0.68 min (HPLC method 4)

The following apparatus and test conditions are used to obtain the datapresented above:

HPLC Analytics HPLC method 1 Column: Sunfire C18, 4.6 × 30 mm, 2.5 μmSupplier: Waters Gradient: % Sol % Sol Flow Temp time [min] [H2O, 0.1%TFA] [Methanol] [ml/min] [° C.] 0.0 95 5 4 60 0.05 95 5 3 60 2.05 0 1003 60 2.10 0 100 4.5 60 2.40 0 100 4.5 60 HPLC method 2 Column: SunfireC18, 3 × 30 mm, 2.5 μm Supplier: Waters Gradient: % Sol % Sol Flow Temptime [min] [H2O, 0.1% TFA] [Methanol] [ml/min] [° C.] 0.0 95 5 1.8 600.25 95 5 1.8 60 1.70 0 100 1.8 60 1.75 0 100 2.5 60 1.90 0 100 2.5 60HPLC method 3 Column: Sunfire, 3 × 30 mm, 2.5 μm Supplier: WatersGradient: % Sol % Sol Flow Temp time [min] [H2O, 0.1% TFA][Acetonitrile] [ml/min] [° C.] 0.00 97 3 2.2 60 0.20 97 3 2.2 60 1.20 0100 2.2 60 1.25 0 100 3 60 1.40 0 100 3 60 HPLC method 4: Column:Sunfire C18, 3 × 30 mm, 2.5 μm Supplier: Waters Gradient: % Sol % SolFlow Temp time [min] [H2O, 0.1% TFA] [Acetonitrile] [ml/min] [° C.] 0.0097 3 2.2 60 0.20 97 3 2.2 60 1.20 0 100 2.2 60 1.25 0 100 3 60 1.40 0100 3 60

Infrared (IR) Spectroscopy

Solid material in KBr pellet. Peaks are given in cm⁻¹ and labelled ‘ss’(very strong), ‘s’ (strong), and ‘m’ (medium).

Thin Layer Chromatography (TLC)

TLC silica glass plates from Merck are used (TLC Silica Gel 60F₂₅₄;1.05729.0001).

The following abbreviations are used above and hereinafter:

ACN Acetonitrile

DCM Methylene chloride

DMF N,N-Dimethylformamide

ESI Electrospray ionization

FA Formic acid

RP-HPLC reversed phase high performance liquid chromatography

r.t. ambient temperature (e.g. 18 to 25° C., preferably 20° C.)

RT retention time

THF Tetrahydrofuran

TBME tert-Butylmethyl ether

TFA Trifluoroacetic acid

TLC Thin layer chromatography

1. A process for the preparation of compounds of general formula (I)

optionally in the form of the tautomers thereof, and optionally the acidaddition salts thereof, wherein R¹ denotes a group of formula (i),

wherein A¹ and A² independently from each other denote N or CH; R^(1.1)denotes hydrogen or a group selected from among chloro, bromo andmethyl, R^(1.2) denotes hydrogen or a group selected from among amino,C₁₋₃-alkyl-NH—, (C₁₋₃-alkyl)₂N— and methyl, or R^(1.1) and R^(1.2)together form an annelated benzo ring; R² denotes hydrogen or a groupselected from among C₁₋₆-alkyl, C₆₋₁₀-aryl-C₁₋₆-alkyl-, heterocyclyl andheterocyclyl-CH₂—, or R² denotes a group of formula (ii) including thepure enantiomers thereof

or R² denotes, with the provisio that A¹ and A² denote N, a group offormula (iii)

wherein W¹ and W² are independently selected from among a bond orC₁₋₈-alkylene; X¹ and X² are independently selected from among a 4- to14-membered heterocyclic group; Y¹ and Y² are independently selectedfrom among a bond, C₁₋₈-alkylene- or —C₁₋₈-alkylamino-; A³ is selectedfrom the group consisting of a C₆₋₁₅-membered aromatic carbocyclicgroup, —CONR⁵—(C₁₋₈-alkylene)-NR⁵CO—, —CO—(C₁₋₈-alkylene)-CO—,—CO—(C₂₋₈-alkenylene)-CO—, —(CO)—,—CO—(C₁₋₈-alkylene)-Z—(C₁₋₈-alkylene)-CO—, —CO—(C₁₋₈-alkylene)-Z—CO—,—CO—Z—CO—, —CO—NR⁵—(C₁₋₈-alkylene)-Z—(C₁₋₈-alkylene)-NR⁵—CO—,—CO—NR⁵—(C₁₋₈-alkylene)-Z—NR⁵—CO—, —CO—NR⁵—Z—NR⁵—CO—, C₃₋₁₅-carbocyclicgroup and a 4- to 14-membered heterocyclic group; Z is selected fromamong C₆₋₁₅-membered aromatic carbocyclic group, C₃₋₁₅-carbocyclic groupand a 4- to 14-membered heterocyclic group; R⁵ is hydrogen orC₁₋₈-alkyl; R³ denotes hydrogen or methyl or R² and R³ together denote—CH₂—CH₂— or —CH₂—CH₂—CH₂—, characterised in that the process comprisesreaction steps (D) and (F), wherein (D) is the reaction of a compound offormula (III) with a compound of formula (VI)

wherein R^(t) denotes C₁₋₄-alkyl; R⁴ denotes a group selected from amongC₁₋₄-alkylthio, 1-pyrazolyl, 1-imidazolyl and 1,2,4-triazol-1-yl, eachoptionally substituted by one or two methyl groups, to form a compoundof formula (IV)

and (F) is the reaction of a compound of formula (IV) with a compound offormula (VII)

while steps (D) and (F) take place successively in the order specified,or characterised in that the process comprises reaction step (E),wherein (E) is the reaction of a compound of formula (III) with acompound of formula (VIII)


2. The process according to claim 1 for the preparation of a compound offormula (I)

optionally in the form of the tautomers thereof, and optionally the acidaddition salts thereof, characterised in that the process comprisesreaction steps (B), (D) and (F), wherein (B) is the reaction of acompound of formula (II)

wherein X⁻ denotes a group selected from among PF₆ ⁻, BF₄ ⁻, SbF₆ ⁻,phenylsulphonate, p-toluenesulphonate, HSO₄ ⁻, (SO₄ ²⁻)/2, FSO₃ ⁻ andF₃CSO₃ ⁻; and R^(t) denotes C₁₋₄-alkyl with a compound of formula (V)R¹—COOH  (V) in the presence of a base, to form a compound of formula(III)

wherein R^(t) denotes C₁₋₄-alkyl; (D) is the reaction of a compound offormula (III) with a compound of formula (VI)

wherein R⁴ denotes a group selected from among C₁₋₄-alkylthio,1-pyrazolyl, 1-imidazolyl and 1,2,4-triazol-1-yl to form a compound offormula (IV)

and (F) is the reaction of a compound of formula (IV) with a compound offormula (VII)

while steps (B), (D) and (F) take place successively in the orderspecified, or characterised in that the process comprises reaction steps(B) and (E), wherein (E) is the reaction of a compound of formula (III)with a compound of formula (VIII)

while steps (B) and (E) take place successively in the order specified.or characterised in that the process comprises reaction steps (C), (D)and (F), wherein (C) is the reaction of a tertiary alcohol selected fromtert-butanol, 2-methyl-2-butanol, 2-methyl-2-pentanol,2-methyl-2-hexanol, 2,3-dimethyl-2-butanol and 2,4-dimethyl-2-pentanoland 5-methyl-1,2-oxazole in the presence of an acid of formula XH and acompound of formula (V) without isolation of a compound of formula (II)to form a compound of formula (III) wherein XH denotes an acid selectedfrom among HPF₆, HBF₄, HSbF₆, phenylsulphonic acid, p-toluenesulphonicacid, H₂SO₄, (H₂SO₄)/2, F₃CCOOH, FSO₃H, and F₃CSO₃H; R^(t) denotesC₁₋₄-alkyl or characterised in that the process comprises reaction steps(C) and (E), while steps (C) and (E) take place successively in theorder specified.
 3. A process for the preparation of compounds ofgeneral formula (III) optionally in the form of the tautomers thereof,and optionally the acid addition salts thereof, characterised in thatthe process comprises reaction steps (B) or (C), wherein (B) is thereaction of a compound of formula (II)

wherein X⁻ denotes a group selected from among PF₆ ⁻, BF₄ ⁻, SbF₆ ⁻,phenylsulphonate, p-toluenesulphonate, HSO₄ ⁻, (SO₄ ²⁻)/2, FSO₃ ⁻ andF₃CSO₃ ⁻; and R^(t) denotes C₁₋₄-alkyl with a compound of formula (V)R¹—COOH  (V) in the presence of a base, to form a compound of formula(III)

wherein R¹ denotes a group of formula (i),

wherein A¹ and A² independently from each other denote N or CH; R^(1.1)denotes hydrogen or a group selected from among chloro, bromo andmethyl, R^(1.2) denotes hydrogen or a group selected from among amino,C₁₋₃-alkyl-NH—, (C₁₋₃-alkyl)₂N— and methyl, or R^(1.1) and R^(1.2)together form an annelated benzo ring; R^(t) denotes C₁₋₄-alkyl; and (C)is the reaction of a tertiary alcohol selected from tert-butanol,2-methyl-2-butanol, 2-methyl-2-pentanol, 2-methyl-2-hexanol,2,3-dimethyl-2-butanol and 2,4-dimethyl-2-pentanol; and5-methyl-1,2-oxazole in the presence of an acid of formula XH and acompound of formula (V) without isolation of a compound of formula (II)to form a compound of formula (III) wherein XH denotes an acid selectedfrom among HPF₆, HBF₄, HSbF₆, phenylsulphonic acid, p-toluenesulphonicacid, H₂SO₄, (H₂SO₄)/2, F₃CCOOH, FSO₃H, and F₃CSO₃H;
 4. The processaccording to claim 3 for the preparation of compounds of general formula(III), wherein R^(t) denotes methyl or ethyl, characterised in that theprocess comprises reaction step (C).
 5. The process according to claim 3for the preparation of compounds of general formula (III),

optionally in the form of the tautomers thereof, and optionally the acidaddition salts thereof, wherein R¹ denotes a group of formula (i),

wherein A¹ and A² independently from each other denote N or CH; R^(1.1)denotes hydrogen or a group selected from among chloro, bromo andmethyl, R^(1.2) denotes hydrogen or a group selected from among amino,C₁₋₃-alkyl-NH—, (C₁₋₃-alkyl)₂N— and methyl; R^(t) denotes methyl orethyl; characterised in that the process comprises reaction steps (A)and (B), wherein (A) is the reaction of a tertiary alcohol selected fromamong tert-butanol or 2-methyl-2-butanol, and 5-methyl-1,2-oxazole withan acid of formula XH to form a compound of formula (II)

wherein R^(t) denotes methyl or ethyl; X⁻ denotes a group selected fromamong PF₆ ⁻, BF₄ ⁻, SbF₆ ⁻, phenylsulphonate, p-toluenesulphonate, HSO₄⁻, (SO₄ ²⁻)/2, FSO₃ ⁻, and F₃CSO₃ ⁻; XH denotes the respective conjugateacid of X⁻; while steps (A) and (B) take place successively in the orderspecified.
 6. A process for the preparation of compounds of generalformula (II),

wherein R^(t) denotes methyl or ethyl; X⁻ denotes a group selected fromamong PF₆ ⁻, BF₄ ⁻, SbF₆ ⁻, phenylsulphonate, p-toluenesulphonate, HSO₄⁻, (SO₄ ²⁻)/2, FSO₃ ⁻, and F₃CSO₃ ⁻. characterised in that the processcomprises reaction step (A), wherein (A) is the reaction of a tertiaryalcohol selected from among tert-butanol and 2-methyl-2-butanol, and5-methyl-1,2-oxazole with an acid of formula XH, wherein XH denotes therespective conjugate acid of X⁻.
 7. A compound of formula (II),

characterised in that X⁻ denotes a group selected from among an anionselected from among PF₆ ⁻, BF₄ ⁻, SbF₆, phenylsulphonate,p-toluenesulphonate, HSO₄ ⁻, (SO₄ ²)/2, FSO₃ ⁻ and F₃CSO₃ ⁻, and R^(t)denotes methyl or ethyl
 8. The compound according to claim 7characterised in that X⁻ denotes PF₆ ⁻ and R^(t) denotes methyl.
 9. Acompound of formula (III.1)

wherein A¹ and A² independently from each other denote N or CH; R^(1.1)denotes hydrogen or a group selected from among chloro, bromo andmethyl, R^(1.2) denotes hydrogen or a group selected from among amino,C₁₋₃-alkyl-NH—, (C₁₋₃-alkyl)₂N— and methyl, or R^(1.1) and R^(1.2)together form an annelated benzo ring.
 10. The compound according toclaim 9 having the formula (III.2)